Study Evaluating The Safety And Efficacy Of PF-03049423 In Subjects With Ischemic Stroke

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The purpose of this study is to evaluate the safety and tolerability of PF-03049423 following multiple dose administration to subjects with ischemic stroke. The study will also evaluate the efficacy of PF-03049423, relative to placebo, in subjects with ischemic stroke following 90 days of therapy. The study will also explore the relationship between PF-03049423 concentration and blood pressure.

Condition or disease

Intervention/treatment

Phase

Ischemic Stroke

Drug: PF-03049423Other: Placebo

Phase 2

Detailed Description:

The interim analysis for the POC study A9541004 demonstrated futility, and the study was stopped on the 6th of November 2013. There were no signals of serious safety concern.

Number of Participants With Any Abnormal Laboratory Test Results (Part 1* and 2) [ Time Frame: Day 1 (Baseline) up to Day 90 ]

The total number of participants with laboratory test abnormalities (without regard to baseline abnormality) was assessed. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together.

Number of Participants With Vital Signs Data Met Criteria of Potential Clinical Concern (Part 1* and 2) [ Time Frame: Day 1 (Baseline) up to follow-up (28 days after Day 90) ]

Number of Participants With Significant Change in Physical Examination Findings (Part 1* and 2) [ Time Frame: Day 1 (Baseline) up to Day 90 ]

The complete physical examination included examination of the skin, eyes, ears, throat, neck, cardiac, respiratory, gastrointestinal, and musculoskeletal systems. The limited physical examination included examination of the cardiac, respiratory, gastrointestinal, and musculoskeletal systems. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together.

Number of Participants With Significant Change in Neurological Examination Findings (Part 1* and 2) [ Time Frame: Day 1 (Baseline) up to Day 90 ]

The complete neurological examination included an assessment of the motor, sensory, cranial nerves, reflexes, mental status and associated motor functions. The limited neurological exam could examine the same categories of neurologic assessments as the full examination, but would differ by the depth in the examination. The examination was required to be done to the extent needed to assess the participant for any potential changes in neurological status, as determined by the Investigator, but had to always include an assessment of motor, vision and hearing. *This endpoint was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for this timeframe were not reported separately, Part 1 and 2 data were reported together.

Number of Participants With Suicidal Behavior and/or Ideation as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (Part 1* and 2) [ Time Frame: Day 7 (Baseline) up to follow up (28 days after Day 90) ]

Data were mapped to Columbia-Classification Algorithm of Suicide Assessment (C-CASA) event codes. C-SSRS assessed if participant experienced: completed suicide (Code 1), suicide attempt (Code 2) (Response of "Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior (Code 3) ("Yes" on "aborted attempt", "interrupted attempt", "preparatory acts or behavior"), suicidal ideation (Code 4) ("Yes" on "wish to be dead", "non-specific active suicidal thoughts", "active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Code 7) ("Yes" on "Has participant engaged in non-suicidal self-injurious behavior"). Number of participants with "Yes" response for any of above mentioned categories was assessed. *This was a primary endpoint for Part 1 (timeframe Days 1 to 14), as data for it were not reported separately, Part 1 and 2 data were reported together.

Percentage of Participants With Modified Rankin Scale (mRS) Less Than or Equal to (<=2) at Day 90 (Part 2) [ Time Frame: Day 90 ]

Change From Baseline in Box and Blocks (B&B) Test at Day 90 for Paretic Hand (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the participant. The participant was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The participant was then required to do the test with his/her paretic hand. The participant was told that if more than 1 block was picked up at a time it was to only count as 1 block. The participant was also told that their fingertips needed to cross the partition for the block to be counted. The performance measure for this task was the number of blocks moved within 1 minute.

Change From Baseline in Box and Blocks (B&B) Test at Day 90 for Paretic to Non-paretic Hand Ratio (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the participant. The participant was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The participant was then required to do the test with his/her paretic hand. The participant was told that if more than 1 block was picked up at a time it was to only count as 1 block. The participant was also told that their fingertips needed to cross the partition for the block to be counted. The performance measure for this task was the number of blocks moved within 1 minute.

Change From Baseline in Hand Grip Strength Test at Day 90 for Paretic and Non-paretic Hands (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The Hand Grip Strength Test measures the maximum isometric strength of the hand and forearm muscles. The participant was required to squeeze the dynamometer with maximum isometric effort while sitting with shoulder adducted and neutrally roated, elbow flexed at 90 degrees and the forearm in neutral position and wrist between 0 to 30 degrees dorsiflexion and a 0 to 15 degrees ulnar deviation. The participant performed this task 3 times with each hand, starting with the non-paretic hand. The performance measure for this task was the average score measured in pounds of pressure exerted.

Change From Baseline in Hand Grip Strength Test at Day 90 for Paretic to Non-paretic Hand Ratio (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The Hand Grip Strength Test measures the maximum isometric strength of the hand and forearm muscles. The participant was required to squeeze the dynamometer with maximum isometric effort while sitting with shoulder adducted and neutrally roated, elbow flexed at 90 degrees and the forearm in neutral position and wrist between 0 to 30 degrees dorsiflexion and a 0 to 15 degrees ulnar deviation. The participant performed this task 3 times with each hand, starting with the non-paretic hand. The performance measure for this task was the average score measured in pounds of pressure exerted.

Percentage of Participants With mRS (0-1) at Day 90 (Part 2) [ Time Frame: Day 90 ]

Percentage of Participants With National Institutes of Health Stroke Scale (NIHSS) (0-1) at Day 90 (Part 2) [ Time Frame: Day 90 ]

The NIHSS is a graded 11-item neurological examination rating speech and language, cognition, visual field deficits, motor and sensory impairments and ataxia used for the clinical assessment of acute stroke therapy. The maximum total score is 42 in a participant with a severe neurological deficit; the minimum score is 0 in a participant without gross neurological deficits.

Change From Baseline in NIHSS at Day 90 (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The NIHSS is a graded 11-item neurological examination rating speech and language, cognition, visual field deficits, motor and sensory impairments and ataxia used for the clinical assessment of acute stroke therapy. The maximum total score is 42 in a participant with a severe neurological deficit; the minimum score is 0 in a participant without gross neurological deficits.

Percentage of Participants With Barthel Index (BI) >= 95 and BI =100 at Day 90 (Part 2) [ Time Frame: Day 90 ]

The BI is an index of independence to score the ability of a participant with a neuromuscular or musculoskeletal disorder to care for him or herself. The index rates a participant's ability on the following 10 activities: feeding, moving from wheelchair to bed, personal toilet, getting on and off toilet, bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. The maximum total score is 100 in a participant without functional impairment; the minimum score is 0 in a participant with major functional impairment.

BI at Day 90 (Part 2) [ Time Frame: Day 90 ]

The BI is an index of independence to score the ability of a participant with a neuromuscular or musculoskeletal disorder to care for him or herself. The index rates a participant's ability on the following 10 activities: feeding, moving from wheelchair to bed, personal toilet, getting on and off toilet, bathing self, walking on level surface, ascending and descending stairs, dressing, controlling bowels and controlling bladder. The maximum total score is 100 in a participant without functional impairment; the minimum score is 0 in a participant with major functional impairment.

Domains of Interest: Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding Sub Test at Day 90 (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The test uses a reference key, the participant had 90 seconds to pair specific numbers with given geometric figures. Responses could be written or oral. The performance measure for this task was the total number of correct responses.

Domains of Interest: Change From Baseline in RBANS Naming Sub Test at Day 90 (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

This test requires the participant to name 10 objects drawn in ink. The tester asked the participant to identify the picture. The participant had 20 seconds to respond to each picture presented. The performance measure was the number of objects named correctly.

The participant was presented with a page that had lines placed across the page. The participant was required to cross out all the lines on the page using their non-paretic hand after the tester had demonstrated what was required by crossing out the center line. The performance measure for this task was the total number of omissions made expressed as a percentage of the total number of items in the test. The test contains 4 variables: (L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%, and (L-R)/(L+R), where L = number of lines crossed on the left side of the paper; R = number of lines crossed on the right side of the paper.

Domains of Interest: Change From Baseline in Line Cancellation Test at Day 90 [(L-R)/(L+R)] (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The participant was presented with a page that had lines placed across the page. The participant was required to cross out all the lines on the page using their non-paretic hand after the tester had demonstrated what was required by crossing out the center line. The performance measure for this task was the total number of omissions made expressed as a percentage of the total number of items in the test. The test contains 4 variables: (L+R)/28 × 100%, (L/14) × 100%, (R/14) × 100%, and (L-R)/(L+R), where L = number of lines crossed on the left side of the paper; R = number of lines crossed on the right side of the paper.

Domains of Interest: Change From Baseline in Recognition Memory Test at Day 90 (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

This test assesses the ability to recognize pictures of objects. The participant was presented a series of pictures, a subset of which were the objects presented in the RBANS Naming Sub Test. After each picture was presented, the participant indicated either manually (ie, affirmative head nod) or verbally whether the picture was seen previously. The participant was given 5 seconds per picture to respond. The performance measure for this task was the total number of pictures correctly identified.

Gait Velocity Test at Day 90 (Part 2) [ Time Frame: Day 90 ]

The 10-meter walk test requires a 20 meter straight path, with 5 meters for acceleration, 10 meters for steady state walking, and 5 meters for deceleration. Markers were placed at the 5 and 15 meter positions along the path. The participant began to walk "at a comfortable pace" at 1 end of the path, and continued walking until he/she reached the other end. The rater used a stopwatch to determine how much time it took for the participant to traverse the 10 meter center of the path, starting the stopwatch as soon as the participant's limb crossed the first marker and stopping the stopwatch as soon as the participant's limb crossed the second marker.

Change From Baseline in Box and Blocks (B&B) Test at Day 90 for Non-paretic Hand (Part 2) [ Time Frame: Day 1 (Baseline), Day 90 ]

The B&B test is a measure of manual dexterity. The B&B apparatus consists of a box divided into 2 sections and 1-inch hardwood blocks. The blocks began in the compartment of the test box to the dominant side of the participant. The participant was required to transfer the blocks one at a time to the other side of the box as quickly as possible in 1 minute using the non-paretic hand. The box was then turned so all the blocks were in the same side as the paretic hand. The participant was then required to do the test with his/her paretic hand. The participant was told that if more than 1 block was picked up at a time it was to only count as 1 block. The participant was also told that their fingertips needed to cross the partition for the block to be counted. The performance measure for this task was the number of blocks moved within 1 minute.

Other Outcome Measures:

All-cause Mortality (Part 2) [ Time Frame: The time began from the participant provided informed consent through 28 calendar days post last administration of investigational product. ]

Deaths regardless causality were reported.

Mortality Directly Related to Stroke (Part 2) [ Time Frame: The time began from the participant provided informed consent through 28 calendar days post last administration of investigational product. ]

Deaths caused by stroke were reported.

Number of Participants With Neuro-worsening (Part 2) [ Time Frame: Day 1 (Baseline) up to Day 90 ]

NIHSS change of 4 points or greater.

Number of Participants With SBP <100 mm Hg or SBP Decline >=30 mm Hg From Immediate Pre-dose Measurement, With or Without Neuro-worsening (Defined as an NIHSS Increase of 4 Points or Greater) Within 2 Hours Post-dose (Part 2) [ Time Frame: Day 1 (Baseline) up to Day 14 ]

Treatment-emergent Adverse Events (AEs) Resulting in Discontinuation of Study Drug (Part 2) [ Time Frame: Day 1 (Baseline) up to follow-up (28 days after Day 90) ]

An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state.

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Ages Eligible for Study:

18 Years to 85 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Diagnosis of ischemic stroke with an onset within 72 hours prior to start of study agent administration, male or female.